Insulin Analogues…and Cancer?
Insulin analogues with different pharmacokinetics were created by inserting point modifications into the amino acid sequence of human insulin, particularly the C-terminus of its beta-chain which is not involved in binding to the insulin receptor (IR). However, these modifications may alter binding affinity for the closely related type 1 insulin-like growth factor (IGF) receptor (IGF1R). Thus, Weinstein et al asked the important question of how these analogues compare to insulin and IGF-I in eliciting IGF-I activities (namely, proliferation and protection from serum starvation-induced apoptosis) in cultured cancer cells.
They studied 2 long-acting insulin analogues (glargine [Lantus®] and detemir [Levemir®]) and 2 short-acting analogues (lispro [Humalog®] and aspart [Novolog®]) in 3 different cell lines: HCT-116 colorectal, PC-3 prostate and MCF-7 breast cancer cells. All experiments were conducted in vitro. Results are summarized in the Table.
HCT-116 cells showed a dose-dependent proliferative response to both glargine and detemir at 72 hours, but not IGF-I (all doses about +21%) nor insulin (all doses negligible effect). The authors then turned to signaling pathways that may underlie the hormonal effects in HCT-116 cells. Basal expression levels of IR and IGF1R were equivalent when measured by Western immunoblotting and immunofluorescent staining. After 10 and 20 minutes of treatment, glargine phosphorylated both IR and IGF1R, and detemir phosphorylated IR but not IGF1R. Glargine further led to increased phosphorylation of both Akt and ERK, representing the 2 major signaling cascades of IR and IGF1R, without changes in the total protein amounts; phosphorylation was maximal at 20 minutes and decreased by 60 minutes. In a test of relative potencies, cells were treated for 30 minutes with each hormone at 50 ng/mL. Glargine and insulin both significantly increased the amount of phosphorylated Akt in comparison to untreated cells, while detemir and IGF-I did not significantly alter Akt phosphorylation. Insulin alone significantly increased ERK phosphorylation.
The authors concluded that at the supra-physiologic doses tested, glargine and detemir have significant IGF-I-like mitogenic activity, which is not shared by insulin. The authors’ warning bears repeating: current evidence shows that neither IGF-I nor insulin (and hence, one would expect the insulin analogues as well) can cause malignant transformation. However, IGF-I does increase the aggressivity of already transformed cells. Thus, the question raised by this paper is whether long-term exposure to the insulin analogues can likewise affect cancer behavior.
It would take a colossal leap to answer the underlying question based on the data of this pilot study. However, the results are intriguing enough to suggest more rigorous investigations are warranted. The high prevalence of both cancer and diabetes in our society, plus the widespread long-term use of these modified insulin analogues, makes the question an important one to answer. If—and this is a big if—it pans out that one or more of the insulin analogues is more stimulatory for cancer behavior, then cancer risk will become yet another factor clinicians must consider in selecting the particular insulin regimen for an individual patient.
Adda Grimberg, MD